Loukovaara Sirpa, Gucciardo Erika, Repo Pauliina, Vihinen Helena, Lohi Jouko, Jokitalo Eija, Salven Petri, Lehti Kaisa
Unit of Vitreoretinal Surgery, Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Research Programs Unit, Genome-Scale Biology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Acta Ophthalmol. 2015 Sep;93(6):512-23. doi: 10.1111/aos.12741. Epub 2015 Apr 21.
Proliferative diabetic retinopathy (PDR) is characterized by ischaemia- and inflammation-induced neovascularization, but the pathological vascular differentiation in PDR remains poorly characterized. Here, endothelial progenitor and growth properties, as well as potential lymphatic differentiation, were investigated in the neovascular membrane specimens from vitrectomized patients with PDR.
The expression of pan-endothelial CD31 (PECAM-1), ETS-related gene (ERG), α-smooth muscle actin (α-SMA), and stem/progenitor cell marker CD117 (c-kit) and cell proliferation marker Ki67 was investigated along with the markers of lymphatic endothelial differentiation (vascular endothelial growth factor receptor (VEGFR)-3; prospero-related homeobox gene-1 (Prox-1), lymphatic vessel endothelial receptor [LYVE)-1 and podoplanin (PDPN)] by immunohistochemistry. Lymphocyte antigen CD45 and pan-macrophage marker CD68 were likewise investigated.
All specimens displayed CD31, ERG and α-SMA immunoreactivity in irregular blood vessels. Unexpectedly, VEGFR3 and Prox-1 lymphatic marker positive vessels were also detected in several tissues. Prox-1 was co-expressed with CD117 in lumen-lining endothelial cells and adjacent cells, representing putative endothelial stem/progenitor cells and pro-angiogenic perivascular cells. Immunoreactivity of CD45 and CD68 was detectable in all investigated diabetic neovessel specimens. PDPN immunoreactivity was also detected in irregular lumen-forming structures, but these cells lacked CD31 and ERG that mark blood and lymphatic endothelium.
Although the inner part of human eye is physiologically devoid of lymphatic vessels, lymphatic differentiation associated with endothelial stem/progenitor cell activation may be involved in the pathogenesis of human PDR. Further studies are warranted to elucidate whether targeting lymphatic factors could be beneficial in the treatment of patients with the sight-threatening forms of DR.
增殖性糖尿病视网膜病变（PDR）的特征是缺血和炎症诱导的新生血管形成，但PDR中病理性血管分化的特征仍不明确。在此，我们对接受玻璃体切除术的PDR患者的新生血管膜标本中的内皮祖细胞和生长特性以及潜在的淋巴管分化进行了研究。
通过免疫组织化学研究了全内皮细胞标志物CD31（血小板内皮细胞黏附分子-1，PECAM-1）、ETS相关基因（ERG）、α-平滑肌肌动蛋白（α-SMA）、干细胞/祖细胞标志物CD117（c-kit）和细胞增殖标志物Ki67的表达，以及淋巴管内皮分化标志物（血管内皮生长因子受体（VEGFR）-3、prospero相关同源盒基因-1（Prox-1）、淋巴管内皮受体[LYVE]-1和血小板源性生长因子受体（PDPN））的表达。同样研究了淋巴细胞抗原CD45和全巨噬细胞标志物CD68。
所有标本在不规则血管中均显示出CD31、ERG和α-SMA免疫反应性。出乎意料的是，在多个组织中也检测到了VEGFR3和Prox-1淋巴管标志物阳性血管。Prox-1与CD117在管腔内衬内皮细胞和相邻细胞中共表达，这些细胞代表假定的内皮干细胞/祖细胞和促血管生成的血管周围细胞。在所有研究的糖尿病新生血管标本中均检测到CD45和CD68的免疫反应性。在不规则的管腔形成结构中也检测到了PDPN免疫反应性，但这些细胞缺乏标记血液和淋巴管内皮的CD31和ERG。
尽管人眼内部在生理上没有淋巴管，但与内皮干细胞/祖细胞激活相关的淋巴管分化可能参与了人类PDR的发病机制。有必要进一步研究以阐明靶向淋巴管因子是否对治疗威胁视力的DR患者有益。
